Of the 20 million Americans suffering from asthma, more than 30% of them are 18 years old or younger, making asthma the most common chronic illness affecting children in the United States. The prevalence of childhood asthma differs greatly between males and females, suggesting that there is a sex specific genetic architecture underlying this complex disease. The overall objective of this proposal is to identify genes and pathways that contribute to sex-specific differences in asthma susceptibility in a birth cohort study of young children who are at an elevated risk for asthma. This research proposal contains three main aims. In Aim 1, genome-wide expression patterns, measured by DMA microarrays, will be used to identify genes that are differentially expressed in rhinovirus stimulated mononuclear cells from children with high levels of interferon-gamma response (i.e. high response children) compared to children with low levels of interferon-gamma response (i.e. low response children). To focus on genes that show sex-specific differences in expression, these experiments will be conducted separately in boys and girls. In Aim 2, SNPs in genes that show differences in expression between high and low responders in one sex, but not both, will be evaluated for their contribution to sexspecific variation in interferon-gamma response and five other asthma-related phenotypes in a cohort of 310 young children. In Aim 3, the SNPs that are both located in differentially expressed genes and associated with asthma-related phenotypic variation will be functionally characterized using an appropriate experimental method, e.g. luciferase reporter assays for promoter region and microRNA binding site SNPs, allele-specific quantification for coding SNPs, and mRNA stability assays for SNPs in 5'and 3'untranslated regions. The results from these three Aims will provide novel insight into the sex-specific mechanisms for gene regulation that may contribute to the striking differences observed in asthma prevalence in adolescent boys and girls. This research will impact public health by providing new information about what causes asthma to be more common in boys before puberty and then more common in girls after puberty. Understanding the cause of this difference between the sexes will lead to new and better ways to treat and prevent asthma in both children and adults.